Current World Health Organization guidelines recommend that infants exposed to HIV at birth should receive cotrimoxazole (TMZ-SMZ) as empiric prophylaxis against Pneumocystis pneumonia for one year without confirmation of H1V infection. However, 70-90% of exposed infants will not become HIV positive but would still take prophylaxis presumptively for one year. CoTrimoxazole in Zambian Infants (TZI) is a three year prospective study measuring population level effects of the WHO's proposal on common pediatric infectious diseases. TZI is funded by USAID and has been actively recruiting patients since July 1, 2003. TZI-MALARIA is a nested case control study within TZI focusing on TMP-SMZ's impact on infant malaria rates, drug resistance, and its effect on the acquistion of malaria immunity during infancy. TZI-MALARIA asks three questions: 1) Will TMP-SMZ exposure reduce rates of asymptomatic parasitemia and clinical malaria during the period of prophylaxis? 2) Will former recipients ofprophylaxis experience higher than expected rates of asymptomatic parasitemia and clinical malaria in the monthsfollowing the cessation of TMP-SMZ prophylaxis? 3) Will TMP-SMZ exposure increase rates of resistance to sulfadoxine-pyrimethamine, a leading antimalarial that is cross-tolerant with TMP-SMZ? These questions will be answered by comparing cumulative rates of malaria during and after the period of prophyalxis, and conducting genetic analsis for SP-resistance markers as a comparison between two groups of infants: Cases - infants exposed to HIV at birth and receiving prophylaxis (but later proven HIV negative at 12 months); and Controls - temporally and geographically matched HIV-unexposed, HIV negative infants, not receiving TMP-SMZ prophylaxis. TZI-MALARIA constitutes the core activity of a five year K23 career development plan. This program integrates class work, mentored research, practical field experience, additional project development, teaching, and other activities derived from the academic environment of Boston University's School of Public Health and my parent organization, the Center for International Health and Development.